In hemodialysis by means of membranes made of regenerated cellulose, besides other phenomena, clear complement activation has also been found. The complement system in blood serum is a complex plasma enzyme system consisting of many components that serves in various ways as a defense against damage from invading foreign cells (bacteria, etc.). If antibodies against the invading organism are present, complement-specific activation can occur from the complex of antibodies with antigenic structures of the foreign cells; otherwise, complement activation occurs by an alternative path through special surface features of the foreign cells. The complement system is based on a number of plasma proteins. After activation, these proteins react specifically with one another in a definite order, and at the end a cell-damaging complex is formed that destroys the foreign cells.
Peptides are liberated from individual components, which initiate inflammatory processes and sometimes also have adverse pathological consequences for the organism. It is assumed that activation in the case of hemodialysis membranes made of regenerated cellulose occurs via the alternative path. This complement activation is determined objectively by determination of the presence of complement fragments C.sub.3a and C.sub.5a.
Reference is made in this regard to the following papers: D. E. Chenoweth et al., Kidney International, Vol. 24, Pages 764 ff, 1983, and D. E. Chenoweth, Asaio-Journal, Vol. 7, Pages 44 ff, 1984.
Although the clinical significance of complement activation has not yet been clarified, it is attempted to prevent it as much as possible during hemodialysis.
Cellulosic membranes have long been used for dialysis and ultrafiltration, and there is a desire to have available cellulosic membranes that show as little complement activation as possible. This applies particularly to cellulosic film membranes.
German Patent Application DE-OS 27 05 735 discloses a dialysis membrane and a method for making this cellulosic dialysis membrane in which one or more cuprammonium cellulose solutions and at least one cuprammonium cellulose solution containing modified cellulose are fed through a spinneret with at least two separately supplied slits. In this process, a solution containing dialkylaminoalkylcellulose is applied to the cellulosic substrate directly during a direct spinning process. The cellulose layer located on the blood side is a completely or partially modified cellulose that contains chemically bonded antithrombogenic substances.
According to German Patent DE-PS 35 24 596, dialysis membranes for hemodialysis are obtained in the form of thin films, tube films, or hollow fibers, with an average degree of substitution of the modified cellulose being in the range of 0.02 to 0.07. The average degree of modification of cellulose modified by substitution means the average number of substituents per glucose anhydride unit of the cellulose constituting the membrane. The desired average degree of substitution is obtained by blending substituted cellulose with non-substituted cellulose, whereupon this blend is then spun in the usual way.
German Patent DE-PS 34 38 531 likewise describes modified cellulosic membranes obtained from mixtures of unmodified cellulose with modified cellulose. The cellulosic membrane can be made by the usual methods described in the literature.
A dialysis membrane with improved biocompatibiiity is already known from German Patent Application DE-OS 35 24 596, which is distinguished by the fact that the average degree of substitution of a modified cellulose is 0.02 to 0.07. This dialysis membrane consists of modified cellulose and preferably contains modified cellulose that has a structure characterized by the formula EQU Cellulose--R'--X--Y
wherein
X is -- ##STR2## and/or --S-- and/or --SO-- and/or --SO.sub.2 -- and/or and/or --CO--O-- and/or --O--; Y is --R and/or --NR.sub.2 and/or --Si(OR").sub.3 and/or --SO.sub.3 H and/or --COOH and/or ##STR3## or their salts; R' is an alkylene group and/or cycloalkylene group and/or arylene group with a total of 1 to 25 carbon atoms; PA1 R" is a hydrogen atom or R; and PA1 R is an alkyl group with 1 to 5 carbon atoms and/or a cycloalkyl group and/or aryl group. PA1 X is ##STR5## wherein R is a hydrogen atom or an alkyl or alkenyl group with 1 to 25 carbon atoms, or a cycloalkyl, tolyl, or phenyl group, PA1 Y is an optionally substituted alkyl, alkenyl, or alkynyl group with 1 to 36 carbon atoms, a cycloalkyl group, or a phenyl, tolyl, or benzyl group, or ##STR6## or --(CH.sub.2).sub.r --COOH, ##STR7## or a (--CH.dbd.CH--COOH) group or an NH-R group, and R has the same meaning as above, PA1 provided that when m=0, n.gtoreq.1.55, when Y is an alkyl group with 1-5 carbon atoms, a --(CH.sub.2).sub.r --COOH group with r=0, 1, or 2, or a phthalic acid group; PA1 the degree of polymerization is more than 400, and which can be made by homogeneous reaction in a mixture of dimethylacetamide and/or N-methylpyrrolidone with LiCl after activation of the cellulose starting material without the presence of LiCl;
This known dialysis membrane is able to reduce blood coagulation, leukopenia, and complement activation to a substantial extent.
German Patent Application P 37 23 897.3 describes cellulose derivatives with the general formula: ##STR4## wherein --Z-- is an optionally substituted alkylene, alkenylene, alkynylene, cycloalkylene, or benzylene or xylylene group; and
and
and
r=1-20 PA2 m=0-2.5 PA2 n=0.2 to 2.95
and
its production and its use for membranes and fibers.
Up to now, however, it has been impossible, or possible only with great effort, to treat a cellulosic film membrane so as to obtain not only a properly functioning cellulosic membrane but one with only minimal complement activation.